Objective: To study the efficacy of combination by cefazolin and ornidazole on preventing postoperative incision infection in rectal cancer patients and its influence on pathogen clearance. Methods: Data of 80 postoperative patients with rectal cancer admitted to the department of rectal medicine from May 2017 to September 2018 were selected, and the patients were divided into control group and observation group with different drugs to prevent postoperative infection, 40 cases in each group. Patients in the control group were given ornidazole to prevent postoperative infection, while patients in the observation group were given cefazolin sodium and ornidazole to prevent postoperative infection.The clinical efficacy and pathogen clearance rate of different drugs were compared between the two groups, also comparing the improvement of inflammatory indicators before and after prophylactic treatment. Results: The total effective rate of the observation group was significantly higher than that of the control group (90.00% vs 72.50%) (P<0.05), and the pathogen clearance rate was significantly higher than that of the control group (P<0.05). CRP, TNF-α and IL-6 were all lower in the observation group than in the control group (P<0.05). Conclusion: The combination of cefazolin sodium and ornidazole have a good effect in preventing postoperative incision infection in rectal cancer patients, effectively removing pathogenic bacteria, controlling the effect on inflammatory indicators, and improving the effect of postoperative incision infection prevention.